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J Physiol Volume 584, Number 3, 907-920, November 1, 2007 DOI: 10.1113/jphysiol.2007.140608
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ALIMENTARY

Gastric motility in soluble guanylate cyclase {alpha}1 knock-out mice

 Gwen Vanneste1, Ingeborg Dhaese1, Patrick Sips2,3, Emmanuel Buys2,3,4, Peter Brouckaert2,3 and Romain A. Lefebvre1

1 Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
2 Department of Molecular Biomedical Research, VIB, Ghent, Belgium
3 Department of Molecular Biology, Ghent University, Ghent, Belgium
4 Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA

The principal target of the relaxant neurotransmitter nitric oxide (NO) is soluble guanylate cyclase (sGC). As the {alpha}1β1-isoform of sGC is the predominant one in the gastrointestinal tract, the aim of this study was to investigate the role of sGC in nitrergic regulation of gastric motility in male and female sGC{alpha}1 knock-out (KO) mice. In circular gastric fundus muscle strips, functional responses and cGMP levels were determined in response to nitrergic and non-nitrergic stimuli. sGC subunit mRNA expression in fundus was measured by real-time RT-PCR; in vivo gastric emptying of a phenol red meal was determined. No changes were observed in sGC subunit mRNA levels between wild-type (WT) and KO tissues. Nitrergic relaxations induced by short trains of electrical field stimulation (EFS) were abolished, while those by long trains of EFS were reduced in KO strips; the latter responses were abolished by 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The relaxations evoked by exogenous NO and the NO-independent sGC activator BAY 41-2272 were reduced in KO strips but still sensitive to ODQ. Relaxations induced by vasoactive intestinal peptide (VIP) and 8-bromo-cGMP were not influenced. Basal cGMP levels were decreased in KO strips but NO, long train EFS and BAY 41-2272 still induced a moderate ODQ-sensitive increase in cGMP levels. Gastric emptying, measured at 15 and 60 min, was increased at 15 min in male KO mice. sGC{alpha}1β1 plays an important role in gastric nitrergic relaxation in vitro, but some degree of nitrergic relaxation can occur via sGC{alpha}2β1 activation in sGC{alpha}1 KO mice, which contributes to the moderate in vivo consequence on gastric emptying.

(Received 12 July 2007; accepted after revision 17 August 2007; first published online 23 August 2007)
Corresponding author R. A. Lefebvre: Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium. Email: romain.lefebvre{at}ugent.be






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